One of the major goals of the field of human genetics is to define the relationship between human genotype and phenotype. Much of our assessment of genotypic variation has been focused on small scale, single-nucleotide events. Our understanding of the molecular basis of disease, however, has begun to reveal that large-scale differences including microduplications and microdeletions contribute significantly to childhood disease, disease susceptibility and normal variation in the population. Despite its importance, there has been no systematic study of this form of genotypic variation. The long-term objective of this proposal is to investigate the pattern and nature of this large-scale variation. Our approach will be directed to regions of the genome that contain highly homologous duplicated sequence and therefore have an increased probability of genomic gain and loss. This proposal is a collaborative effort which brings together expertise in genome structure, array comparative genomic hybrdization technology and mental retardation. The specific aims of this proposal are i) to identify and validate all intrachromosomally duplicated regions within the human genome, 2)to develop a set of large-insert clones bracketed by duplicated sequence to be placed on a CGH microarray platform for genome-wide screening, 3)to assess copy number variation within both normal individuals and children with idiopathic mental retardation and 4)to validate the extent, frequency and inheritance pattern of these large structural _polymorphisms _. This project aims to address two fundamental questions: What is the nature and frequency of duplication-mediated structural polymorphisms within the human genome? Are there an excess of de novo events among children with mental retardation and congenital birth defects? PERFORMANCESITE(S) (organization,city, state) Case Western Reserve University and University Hospitals of Cleveland, Department of Genetics, School of Medicine Cleveland, OH 44060 University of California San Francisco Cancer Center, School of Medicine San Francisco, CA 94143 Oxford University Wellcome Trust Center for Human Genetics Oxford, UK KEY PERSONNEL. See instructions. Use continuationpages as needed to provide the required information in the format shownbelow. Startwith Principal Investigator. List all other key personnel in alphabetical order, last namefirst. Name Organization Role on Project Eichler, Evan E. Ph.D. Case Western Reserve University Principal Investigator Albertson, Donna Ph.D. University of California San Francisco Collaborator Flint, Jonathan, MD Oxford University Collaborator Knight, Samantha, Ph.D. Oxford University Collaborator Pinkel, Daniel, Ph.D. University of Califronia San Francisco Collaborator Schwartz, Stuart, Ph.D. Case Western Reserve University Co-prinicipal investigator [] PHS 398 (Rev. 05/01) Page 2 FormPage 2 [] Principal Investigator/Program Director (Last, first, middle): Eichler, Evan E., Ph.D. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page .................................................................................................................................................. 1 Description,